D-Glucose, often in combination with certain amino acids, is the major physiological stimuli for insulin secretion. Net insulin production and glucose homeostasis, however, is regulated by a number of other substances, including several neurotransmitters that act directly on β-cells and indirectly through other target tissues. Many of these substances function as amplifying agents that have little or no effect by themselves, but enhance the signals triggered by the β-cell glucose sensing apparatus.
For example, during the cephalic phase of digestion, acetylcholine (ACh) is released via parasympathetic nerve terminals ending in islets. β-cells express the M3 muscarinic receptor and respond to exogenous ACh with increased inositol phosphate production, which in turn facilitates Na+ ion exit and calcium ion entry. This results in augmented insulin vesicle exocytosis. The amino acid glutamate, the major excitatory neurotransmitter in the central nervous system, can be found in both α- and β-cells of the endocrine pancreas. It is stored in glucagon- or insulin-containing granules, and appears to enhance insulin secretion when it is released. The presence of metabotropic glutamate receptors on α- and β-cells themselves suggests the presence of both autocrine and paracrine circuits within islet tissue involved in the regulation of insulin secretion.
Other neurotransmitters, such as the monoamines epinephrine and norepinephrine, released in circulation, may act to suppress glucose-stimulated insulin secretion by direct interaction with adrenoreceptors expressed (mainly the α-2 receptor) on pancreatic β-cells. β-cells of the endocrine pancreas also express dopamine receptors (D2) and respond to exogenous dopamine with inhibited glucose-stimulated insulin secretion. Purified islet tissue itself is a rich source of monoamines, and has been shown to contain 5-hydroxytryptamine, epinephrine, norepinephrine and dopamine.
β-cells also have the biosynthetic apparatus to create, dispose of, and store specific neurotransmitters. For example, islet tissue has been shown to include (a) tyrosine hydroxylase, the enzyme responsible for catalyzing the conversion of L-tyrosine to dihydroxyphenylalanine (DOPA), a precursor of dopamine, (b) L-DOPA decarboxylase, responsible for converting L-DOPA to dopamine, and (c) dopamine β-hydroxylase, the enzyme that catalyzes the conversion of dopamine to norepinephrine.
In addition, L-3,4-dihydroxyphenylalanine (L-DOPA) is rapidly converted to dopamine in islet β-cells. Monoamine oxidase (MAO) is a catabolic enzyme responsible for the oxidative de-amination of monoamines, such as dopamine and catecholamines, and maintains the homeostasis of monoamine-containing synaptic vesicles. The possible role of MAO in islet function has been studied, and MAO has been detected in the large majority of pancreatic islet cells, including β-cells. Interestingly, some MAO inhibitors have been shown to antagonize glucose-induced insulin secretion. The secretory granules of pancreatic β-cells have been documented to have the ability to store substantial amounts of calcium, dopamine, and serotonin therein.
In the central nervous system, the storage of monoamine neurotransmitters in secretory organelles is mediated by vesicular amine transporters. These molecules are expressed as integral membrane proteins of the lipid bilayer of secretory vesicles in neuronal and endocrine cells. By way of an electrochemical gradient, the vesicular amine transporters exchange one cytosolic monoamine, such as dopamine, for two intravesicular protons functioning to package neurotransmitters for later discharge into the synaptic space. Accordingly, vesicular monoamine transporters (VMAT) are members of the vesicular transporter family responsible for the uptake and secretion of monoamine neurotransmitters in neurons and endocrine cells. Zheng G, et al., AAPS J. 2006, 8(4), 689.
Two isoforms of VMAT (type 1 and 2) have been cloned, and both immunohistochemistry and gene expression studies have shown that the insulin-producing beta cells in the pancreas only express the VMAT2 isoform. Anlauf M., et al., J Histochem Cytochem. 2003, 51, 1027. The feasibility of noninvasive measurement of beta cell mass has been demonstrated both in humans and rodents by positron emission tomography (PET) using VMAT2 as the biomarker and its specific antagonist dihydrotetrabenazine (DTBZ) as the tracer. Souza F., et al., J Clin Invest. 2006, 116(6), 1506; Murthy R, et al., Eur J Nucl Med Mol Imaging 2008, 35(4), 790-797. Studies have shown that VMAT2 plays an important functional role in the regulation of insulin secretion in beta cells. Raffo A., et al., J of Endocrinol 2008, 198, 141-49. VMAT2 antagonist tetrabenazine (TBZ) and its active metabolite DTBZ are potent hypoglycemic agents that stimulate insulin secretion in vitro and improve glucose tolerance in normal and diabetic rats. Raffo A., et al., J of Endocrinol 2008, 198, 141-49.
Diabetes mellitus is a growing epidemic affecting hundreds of millions worldwide. Despite the existence of new classes of hypoglycemic agents, the medical need remains largely unmet and innovative therapeutics are still needed. VMAT2 antagonists have potential in the management of diabetes and hyperglycemia.